Sexually transmitted diseases (STDs) are among the most common infectious diseases in humans. Local immune responses, especially the mucosal immunoglobulins (Igs), provide the first line of defense against primary mucosal infections. IgG is a dominant Ig class in the mucosal secretions of the human genital tract, where it predominates over IgA. Despite the abundance of human IgG, surprisingly less is known about how IgG is secreted into the genital lumen and the exact role of IgG in preventing sexually transmitted pathogens. Our long-term goal is to elucidate the molecular mechanisms of IgG transport in the genital tract and the role of IgG immunity to sexually transmitted pathogens. The specific hypotheses are that FcRn mediates IgG transcytosis and plays a major role in mucosal protection, and that FcRn can deliver an antigen fused to an IgG Fc fragment across the female genital tract to gain access to underlying antigen-presenting cells. These hypotheses were based on the observations that 1) FcRn can mediate the bi-directional transport (apical to basolateral, or vice versa) of IgG across intestinal or placental epithelial cell lines, 2) our recent study showed that human and rodent FcRn were functionally expressed in epithelial cells derived from the human female genital tract, 3) FcRn binds IgG only at acidic pH;whereas, the vagina exhibits acidic pH, 4) the levels of IgG in the female genital tract can be changed over the course of the estrous cycle. Our new data showed that hormone significantly regulated the FcRn expression. Based on these observations, the experimental focus of this proposal is on the understanding of IgG transport and IgG-mediated immunity to genital infections. The specific aims are to: 1. Determine the FcRn-meidated IgG transcvtosis in the reproductive tract;2. Determine FcRn-mediated IgG immunity to primary infections of sexually transmitted pathogens, such as herpes simplex virus-2: 3. Determine the ability of FcRn to deliver IgG Fc-fused antigens, HSV-2 gD-Fc, across the genital mucosal barrier to generate protective immunity. These studies will increase our presently-limited understanding of immune protection for the genital tract, and will provide the basic knowledge essential for the prevention of other STDs, including human immunodeficiency virus, vaginitis, syphilis, gonorrhea, papillomavirus, Candida albican, etc.